The role of Eph receptors in cancer and how to target them: novel approaches in cancer treatment.

Introduction: Erythropoietin-producing human hepatocellular (Eph) receptors are among the largest family of tyrosine kinases that are divided into two classes: EphA and EphB receptors. Over the past two decades, their role in cancer has become more evident. Areas covered: There is a need for new anticancer treatments and more insight in the emerging role of Eph receptors in cancer. Molecular mechanisms underlying the pro-tumorigenic effects of Eph receptors could be exploited for future therapeutic strategies. This review describes the variability in expression levels and different effects on oncogenic and tumor suppressive downstream signaling of Eph receptors in various cancer types, and the small molecules, antibodies and peptides that target these receptors. Expert opinion: The complexity of Eph signaling is a challenge for the definition of clear targets for cancer treatment. Nevertheless, numerous drugs that target EphA2 and EphB4 are currently in clinical trials. However, some Eph targeted drugs also inhibit other tyrosine kinases, so it is unclear to what extent the targeting of Eph receptors contributes to their efficacy. Future research is warranted for an improved understanding of the full network in which Eph receptors function. This will be critical for the improvement of the anticancer effects of drugs that target the Eph receptors

CX-5461 Inhibits Pancreatic Ductal Adenocarcinoma Cell Growth, Migration and Induces DNA Damage

Background: Inhibition of ribosome biogenesis has recently emerged as a promising strategy for the treatment of metastatic tumors. The RNA polymerase I inhibitor CX-5461 has shown efficacy in a panel of cancer types and is currently being tested in clinical trials. However, further preclinical studies to unravel molecular mechanisms underlying the activity of this drug are warranted. Methods: In this study, we have investigated the effects of CX-5461 on cell growth and migration of pancreatic cancer cells by the sulforhodamine-B and wound healing assay, respectively. Furthermore, we assessed the expression of epithelial-to-mesenchymal transition (EMT) genes by qRT-PCR, while protein expression of DNA damage marker phospho-H2A.X was studied by Western blot and immunofluorescence. Results: CX-5461 inhibits pancreatic cancer cell growth in the nanomolar range and inhibits the migratory capability of the cells. Additionally, CX-5461 induced expression of EMT factor SNAI1 and caused DNA double-strand breaks as measured by increased expression of phospho-H2A.X. Conclusion: This study demonstrated that CX-5461 is active against pancreatic cancer cells and modulation of EMT factors, as well as increased expression of phospho-H2A.X, support further pre-/clinical investigations, including the analyses of these markers

The role of Eph receptors in cancer and how to target them: novel approaches in cancer treatment

Introduction: Erythropoietin-producing human hepatocellular (Eph) receptors are among the largest family of tyrosine kinases that are divided into two classes: EphA and EphB receptors. Over the past two decades, their role in cancer has become more evident. Areas covered: There is a need for new anticancer treatments and more insight in the emerging role of Eph receptors in cancer. Molecular mechanisms underlying the pro-tumorigenic effects of Eph receptors could be exploited for future therapeutic strategies. This review describes the variability in expression levels and different effects on oncogenic and tumor suppressive downstream signaling of Eph receptors in various cancer types, and the small molecules, antibodies and peptides that target these receptors. Expert opinion: The complexity of Eph signaling is a challenge for the definition of clear targets for cancer treatment. Nevertheless, numerous drugs that target EphA2 and EphB4 are currently in clinical trials. However, some Eph targeted drugs also inhibit other tyrosine kinases, so it is unclear to what extent the targeting of Eph receptors contributes to their efficacy. Future research is warranted for an improved understanding of the full network in which Eph receptors function. This will be critical for the improvement of the anticancer effects of drugs that target the Eph receptors

CX-5461 Inhibits Pancreatic Ductal Adenocarcinoma Cell Growth, Migration and Induces DNA Damage

BACKGROUND: Inhibition of ribosome biogenesis has recently emerged as a promising strategy for the treatment of metastatic tumors. The RNA polymerase I inhibitor CX-5461 has shown efficacy in a panel of cancer types and is currently being tested in clinical trials. However, further preclinical studies to unravel molecular mechanisms underlying the activity of this drug are warranted. METHODS: In this study, we have investigated the effects of CX-5461 on cell growth and migration of pancreatic cancer cells by the sulforhodamine-B and wound healing assay, respectively. Furthermore, we assessed the expression of epithelial-to-mesenchymal transition (EMT) genes by qRT-PCR, while protein expression of DNA damage marker phospho-H2A.X was studied by Western blot and immunofluorescence. RESULTS: CX-5461 inhibits pancreatic cancer cell growth in the nanomolar range and inhibits the migratory capability of the cells. Additionally, CX-5461 induced expression of EMT factor SNAI1 and caused DNA double-strand breaks as measured by increased expression of phospho-H2A.X. CONCLUSION: This study demonstrated that CX-5461 is active against pancreatic cancer cells and modulation of EMT factors, as well as increased expression of phospho-H2A.X, support further pre-/clinical investigations, including the analyses of these markers

Targeting the Ribosome Biogenesis Key Molecule Fibrillarin to Avoid Chemoresistance

BACKGROUND: Inherent or acquired chemo resistance in cancer patients has been a perpetual limitation in cancer treatment. Expanding knowledge on essential cellular processes opens a new window for therapeutic targeting. Ribosome biogenesis is a process that shows potential due to its fundamental role in cell development and contribution to tumorigenesis as a result of its upregulation. Inhibiting components of ribosome biogenesis has been explored and has shown interesting results. Yet, an important key component, methyltransferase Fibrillarin (FBL), which influences both the abundance and composition of ribosomes, has not been exploited thus far. METHODS: In this literature review, we describe relevant aspects of ribosome biogenesis in cancer to emphasize the potential of FBL as a therapeutic target, in order to lower the genotoxic effects of anti-cancer treatment. RESULTS: Remarkably, the amplification of the 19q13 cytogenetic band, including the gene coding for FBL, correlated to cell viability and resistance in pancreatic cells as well as to a trend toward a shorter survival in pancreatic cancer patients. Targeting ribosome biogenesis, more specifically compared to the secondary effects of chemotherapeutics such as 5-fluorouracil or oxaliplatin, has been achieved by compound CX-5461. The cell dependent activity of this Pol I inhibitor has been reported in ovarian cancer, melanoma and leukemia models with active or mutated p53 status, presenting a promising mechanism to evade p53 resistance. CONCLUSION: Targeting critical ribosome biogenesis components in order to decrease the genotoxic activity in cancer cell looks promising. Hence, we believe that targeting key protein rRNA methyltransferase FBL shows great potential, due to its pivotal role in ribosome biogenesis, its correlation to an improved survival rate at low expression in breast cancer patients and its association with p53

MicroRNAs as a drug resistance mechanism to targeted therapies in EGFR-mutated NSCLC: Current implications and future directions

The introduction of EGFR-tyrosine kinase inhibitors (TKIs) has revolutionized the treatment and prognosis of non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations. However, these patients display disease progression driven by the onset of acquired mechanisms of drug resistance that limit the efficacy of EGFR-TKI to no longer than one year. Moreover, a small fraction of EGFR-mutated NSCLC patients does not benefit from this targeted treatment due to primary (i.e. intrinsic) mechanisms of resistance that preexist prior to TKI drug treatment. Research efforts are focusing on deciphering the distinct molecular mechanisms underlying drug resistance, which should prompt the development of novel antitumor agents that surmount such chemoresistance modalities. The capability of microRNAs (miRNAs) to regulate the expression of many oncogenic pathways and their central role in lung cancer progression, provided new directions for research on prognostic biomarkers, as well as innovative tools for predicting patients’ response to systemic therapies. Recent evidence suggests that modulation of key miRNAs may also reverse oncogenic signaling pathways, and potentiate the cytotoxic effect of anti-cancer therapies. In this review, we focus on the putative emerging role of miRNAs in modulating drug resistance to EGFR-TKI treatment in EGFR-mutated NSCLC. Moreover, we discuss the current implications of miRNAs analyses in the clinical setting, using both tissue and liquid biopsies, as well as the future potential use of miRNA-based therapies in overcoming resistance to targeted agents like TKIs

Antibiotics and Adverse Events in Patients with Pancreatic Cancer Treated with Gemcitabine: Looking for Novel Clinical and Preclinical Insights

This letter to the editor remarks on a recently published article reporting on gemcitabine‐related adverse events associated with antibacterial use, focusing on key points for further consideration